The E2F1-HOXB9/PBX2-CDK6 axis drives gastric tumorigenesis and serves as a therapeutic target in gastric cancer.

Homeobox genes include HOX and non-HOX genes. HOX proteins play fundamental roles during ontogenesis by interacting with other non-HOX gene-encoded partners and performing transcriptional functions, whereas aberrant activation of HOX family members drives tumorigenesis. In this study, gastric cancer (GC) expression microarray data indicated that HOXB9 is a prominent upregulated HOX member in GC samples significantly associated with clinical outcomes and advanced TNM stages. However, the functional role of HOXB9 in GC remains contradictory in previous reports, and the regulatory mechanisms are elusive. By in silico and experimental analyses, we found that HOXB9 was upregulated by a vital cell cycle-related transcription factor, E2F1. Depleting HOXB9 causes G1-phase cell cycle arrest by downregulating CDK6 and a subset of cell cycle-related genes. Meanwhile, HOXB9 contributes to cell division and maintains the cytoskeleton in GC cells. We verified that HOXB9 interacts with PBX2 to form a heterodimer, which transcriptionally upregulates CDK6. Knocking down CDK6 can phenocopy the tumor-suppressive effects caused by HOXB9 depletion. Blocking HOXB9 can enhance the anti-tumor effect of CDK6 inhibitors. In conclusion, we elucidate the oncogenic role of HOXB9 in GC and reveal CDK6 as its potent downstream effector. The E2F1-HOXB9/PBX2-CDK6 axis represents a novel mechanism driving gastric carcinogenesis and conveys prognostic and therapeutic implications. © 2023 The Pathological Society of Great Britain and Ireland.

Cancer-associated fibroblasts potentiate colorectal cancer progression by crosstalk of the IGF2-IGF1R and Hippo-YAP1 signaling pathways.

Colorectal cancer (CRC) is one of the most common cancers worldwide. The tumor microenvironment exerts crucial effects in driving CRC progression. Cancer-associated fibroblasts (CAFs) serve as one of the most important tumor microenvironment components promoting CRC progression. This study aimed to elucidate the novel molecular mechanisms of CAF-secreted insulin-like growth factor (IGF) 2 in colorectal carcinogenesis. Our results indicated that IGF2 was a prominent factor upregulated in CAFs compared with normal fibroblasts. CAF-derived conditioned media (CM) promoted tumor growth, migration, and invasion of HCT 116 and DLD-1 cells. IGF1R expression is significantly increased in CRC, serving as a potent receptor in response to IGF2 stimulation and predicting unfavorable outcomes for CRC patients. Apart from the PI3K-AKT pathway, RNA-seq analysis revealed that the YAP1-target signature serves as a prominent downstream effector to mediate the oncogenic signaling of IGF2-IGF1R. By single-cell RNA sequencing (scRNA-seq) and immunohistochemical validation, IGF2 was found to be predominantly secreted by CAFs, whereas IGF1R was expressed mainly by cancer cells. IGF2 triggers the nuclear accumulation of YAP1 and upregulates YAP1 target signatures; however, these effects were abolished by either IGF1R knockdown or inhibition with picropodophyllin (PPP), an IGF1R inhibitor. Using CRC organoid and in vivo studies, we found that cotargeting IGF1R and YAP1 with PPP and verteporfin (VP), a YAP1 inhibitor, enhanced antitumor effects compared with PPP treatment alone. In conclusion, this study revealed a novel molecular mechanism by which CAFs promote CRC progression. The findings highlight the translational potential of the IGF2-IGF1R-YAP1 axis as a prognostic biomarker and therapeutic target for CRC. © 2022 The Pathological Society of Great Britain and Ireland.

Targeting YAP1/TAZ in nonsmall-cell lung carcinoma: From molecular mechanisms to precision medicine.

Accumulating evidence has underscored the importance of the Hippo-YAP1 signaling in lung tissue homeostasis, whereas its deregulation induces tumorigenesis. YAP1 and its paralog TAZ are the key downstream effectors tightly controlled by the Hippo pathway. YAP1/TAZ exerts oncogenic activities by transcriptional regulation via physical interaction with TEAD transcription factors. In solid tumors, Hippo-YAP1 crosstalks with other signaling pathways such as Wnt/ß-catenin, receptor tyrosine kinase cascade, Notch and TGF-ß to synergistically drive tumorigenesis. As YAP1/TAZ expression is significantly correlated with unfavorable outcomes for the patients, small molecules have been developed for targeting YAP1/TAZ to get a therapeutic effect. In this review, we summarize the recent findings on the deregulation of Hippo-YAP1 pathway in nonsmall cell lung carcinoma, discuss the molecular mechanisms of its dysregulation in leading to tumorigenesis, explore the therapeutic strategies for targeting YAP1/TAZ, and provide the research directions for deep investigation. We believe that detailed delineation of Hippo-YAP1 regulation in tumorigenesis provides novel insight for accurate therapeutic intervention.

[Endobronchial lipoma: report of 2 cases and review of the Chinese literature].

OBJECTIVE: To describe the epidemiology of endobronchial lipoma and to propose appropriate diagnostic and therapeutic policies for this tumor. METHODS: Two cases of endobronchial lipoma were presented and 38 cases reported in literatures published in mainland China were reviewed. RESULTS: Thirty-one male and 9 female patients were included, with a mean age of (53 ± 11) years. The overwhelming majority of the tumors (n = 37) were found in the trachea, left or right main bronchi and lobular bronchi. The main symptoms included cough, dyspnea, fever and hemoptysis. Chest CT showed fat or soft tissue density endobronchial masses in 75% (21/28) cases. Eight patients (22.2%) were diagnosed by histological study of the transbronchial biopsy specimen. Thirty-two patients underwent surgical resection. Bronchoscopic resection was carried out in 7 cases. CONCLUSION: CT and bronchoscope are highly useful diagnostic tools for endobronchial lipoma. Bronchoscopic resection should be considered as the first choice of treatment for endobronchial lipoma.

[Clinicopathologic study of Churg-Strauss syndrome].

OBJECTIVE: To study the clinical and pathologic features of Churg-Strauss syndrome (CCS). METHODS: Three cases of Churg-Strauss syndrome, including 1 autopsy case and 2 cases with open thoracoscopic lung biopsy, were retrospectively reviewed. All the tissue samples were formalin-fixed, paraffin-embedded and stained with hematoxylin and eosin. RESULTS: The first patient was a 68-year-old man who had history of asthma for 4 years, with recent exacerbation and chest pain for 2 weeks. Patient died 1 day after admission due to myocarditis and myocardial infarction. He did not have peripheral eosinophilia, skin or paranasal sinus pathology. CSS represented an incidental autopsy finding and he had never been treated with corticosteroid before. The other 2 patients were a 58-year-old male and a 12-year-old female, respectively. Both had history of asthma, peripheral eosinophilia and lung consolidations on computed tomographic examination. Pathologically, all cases showed vasculitis, perivascular allergic-type granulomas, eosinophilic pneumonia and asthmatic bronchitis. CONCLUSIONS: Thorough understanding of the clinical and pathologic criteria is essential for arriving at a correct diagnosis of CSS. Although some patients may present with atypical symptoms, lung biopsies often reveal the classic histologic findings which include vasculitis and perivascular allergic granuloma formation.

[Questionnaire survey of guideline implementation for community acquired pneumonia with retrospective analysis of the empiric treatment in 490 patients].

OBJECTIVE: To assess physicians' awareness and use of guidelines for community-acquired pneumonia (CAP) published by Chinese Society of Respiratory Diseases (CSRD) and American Thoracic Society (ATS), and to investigate influences of the guidelines on the prognosis of patients with CAP. METHOD: A total of 210 self-completion questionnaires about CAP guidelines were received from doctors of six hospitals in Beijing. In addition, 490 serial cases of CAP collected from these hospitals admitted from January 2002 to December 2003 were retrospectively analyzed. RESULTS: Most doctors had limited knowledge about atypical pathogens. For pulmonary physicians, only 46% (97/210) reported using the CSRD guideline. 82.4% of the doctors preferred to give initial empiric antibiotic therapy according to the patients' conditions. 79.5% (167/210) of the doctors ordered examination of the pathogens routinely and 84.3% (177/210) of them admitted its usefulness for choosing antibiotics. 84.5% (414/490) of the patients responded well to the initial empiric treatment. Patients who were treated according to the guidelines of CSRD and ATS were 229 cases and 131 cases respectively. There was no significant difference in the prognosis between patients who were treated according to the guideline and those who were not. There was no significant difference in the prognosis between cases with definite pathogens and cases without. CONCLUSIONS: The results indicate low levels of awareness and use of guidelines for the management of CAP. Fewer than half of the patients were treated according to the guidelines. However, the treatments were effective in most of the patients, and there was no significant difference in the prognosis between patients who were treated according to the guideline and those who were not, because broad-spectrum antibiotics were overused. More effective guideline implementation strategies are needed to encourage compliance with practice guidelines for the management of CAP.

[The effect of montelukast, a leukotriene antagonist, on improvement of exercise-induced bronchoconstriction].

OBJECTIVE: To study the efficacy of montelukast, a cysteinyl leukotriene receptor antagonist, in the treatment and prevention of exercise-induced bronchoconstriction (EIB) in mild asthmatic patients and patients with exercise-induced asthma (EIA). METHODS: Thirty mild asthmatic patients with positive standardized exercise challenge test were enrolled. The subjects received montelukast 10 mg once daily in the evening. Standard exercise challenge was performed before, three days and twenty-eight days after the administration of the drug. The end points included: (1) Area under the percent fall in forced expiratory volume in one second (FEV1) versus time curve (AUC0 to approximately 60 min); (2) Time of recovery to within 5% of the pre-exercise baseline FEV1 value; and (3) Maximal percent fall in FEV1 from pre-exercise baseline. RESULTS: Montelukast caused significant reduction in AUC0 to approximately 60 min, which was (39 +/- 21)%.min before treatment as compared to (13 +/- 14)%.min and (12 +/- 14)%.min three days and twenty-eight days respectively after the treatment with montelukast. Time of recovery to within 5% of the pre-exercise baseline FEV1 value were (51 +/- 36) min, (26 +/- 28) min and (25 +/- 33) min respectively. The mean maximal percentage decrease in FEV1 after exercise was 44.4% before treatment, 26.8% and 18.2% following montelukast. FEV1 and peak expiratory flow rate (PEFR) were maintained to nearly normal during all the study. Inhale corticosteroid did not prevent EIB/EIA. CONCLUSION: Montelukast attenuates and protects against EIB/EIA.